Nicotinamide, a SIRT1 inhibitor, inhibits differentiation and facilitates expansion of hematopoietic progenitor cells with enhanced bone marrow聽homing and engraftment

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• 作者：Tony Peled^a ; ^{Tony@gamida-cell.com} ; ; Hadas Shoham^a ; Dorit Aschengrau^a ; Dima Yackoubov^a ; Gabi Frei^a ; Noga Rosenheimer G^a ; Batya Lerrer^b ; Haim Y. Cohen^b ; Arnon Nagler^c ; Eitan Fibach^d ; Amnon Peled^e
• 刊名：Experimental Hematology
• 出版年：2012
• 期刊代码：100_0301472x
• 类别：med
• 出版时间：April, 2012
• 卷：40
• 期：4
• 页码：342-355.e1
• 文件大小：1599 K

摘要

Strategies that increase homing to the bone marrow and engraftment efficacy of ex聽vivo expended CD34⁺ cells are expected to enhance their clinical utility. Here we report that nicotinamide (NAM), a form of vitamin B-3, delayed differentiation and increased engraftment efficacy of cord blood-derived human CD34⁺ cells cultured with cytokines. In the presence of NAM, the fraction of CD34⁺CD38^{鈭?/sup> cells increased and the fraction of differentiated cells (CD14+, CD11b+, and CD11c+) decreased. CD34+ cells cultured with NAM displayed increased migration toward stromal cell derived factor-1 and homed to the bone marrow with higher efficacy, thus contributing to their increased engraftment efficacy, which was maintained in competitive transplants with noncultured competitor cells. NAM is a known potent inhibitor of several classes of ribosylase enzymes that require NAD for their activity, as well as sirtuin (SIRT1), class III NAD+-dependent-histone-deacetylase. We demonstrated that EX-527, a specific inhibitor of SIRT1 catalytic activity, inhibited differentiation of CD34+ cells similar to NAM, while specific inhibitors of NAD-ribosylase enzymes did not聽inhibit differentiation, suggesting that the NAM effect is SIRT1-specific. Our findings suggest聽a critical function of SIRT1 in the regulation of hematopoietic stem cell activity and imply the聽clinical utility of NAM for ex聽vivo expansion of functional CD34+ cells.}